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Future perspectives in diabesity treatment: Semaglutide, a glucagon‑like peptide 1 receptor agonist (Review)

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Abstract

Given their endemic prevalence in the past decades, obesity and type 2 diabetes mellitus (T2DM) have become a major sanitary burden with an important economic impact. Novel treatment options have been designed with the aim of reducing the numerous complications associated with these metabolic disorders, as well as reducing morbidity and mortality and improving the quality of life of those who suffer from these disorders. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are among the most modern therapeutics that target 'diabesity', a term used to describe the pathophysiological link between obesity and T2DM. Their glucose-lowering effects are mainly attributed to glucose-dependent insulin secretion, glucagon inhibition and decreased gastric emptying. Given the effects on the central nervous system, GLP-1 RA usage may lead to body weight reduction. GLP-1 RAs are classified based on their pharmacokinetic properties as short- and long-acting agents, with both types being administered by subcutaneous injection. The latest agent from this drug class approved for use in T2DM is semaglutide, a long-acting compound that is the only GLP-1 RA available as an oral pill. The present narrative review highlights the most recently published data on the effects and safety of semaglutide in diabetic obesity, also emphasizing its cardiovascular benefits and potential side effects. In addition, an overview of the role of semaglutide in the treatment of non-diabetic obesity is provided.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021
Abstract. Given their endemic prevalence in the past decades,
obesity and type 2 diabetes mellitus (T2DM) have become a
major sanitary burden with an important economic impact.
Novel treatment options have been designed with the aim
of reducing the numerous complications associated with
these metabolic disorders, as well as reducing morbidity and
mortality and improving the quality of life of those who suffer
from these disorders. Glucagon‑like peptide 1 receptor agonists
(GLP‑1 RAs) are among the most modern therapeutics that ta rget
‘diabesity’, a term used to describe the pathophysiological link
between obesity and T2DM. Their glucose‑lowering effects
are mainly attributed to glucose‑dependent insulin secretion,
glucagon inhibition and decreased gastric emptying. Given the
effects on the central nervous system, GLP‑1 RA usage may
lead to body weight reduction. GLP‑1 RAs are classied based
on their pharmacokinetic properties as short‑ and long‑acting
agents, with both types being administered by subcutaneous
injection. The latest agent from this drug class approved for
use in T2DM is semaglutide, a long‑acting compound that
is the only GLP‑1 RA available as an oral pill. The present
narrative review highlights the most recently published data
on the effects and safety of semaglutide in diabetic obesity,
also emphasizing its cardiovascular benets and potential side
effects. In addition, an overview of the role of semaglutide in
the treatment of non‑diabetic obesity is provided.
Contents
1. Introduction
2. GLP‑1‑biological effects and development of GLP‑1 RAs
3. Semaglutide in diabesity and non‑diabetic obesity
4. Semaglutide‑side effects and cautions
5. Future considerations
6. Conclusions
1. Introduction
Obesity is a metabolic disease with increasing prevalence
over the past decades, becoming an important economic and
health care burden (1). In 2016, the World Health Organization
estimated that worldwide more than 650 million adults
were obese (2). Obesity is associated with multiple chronic
comorbidities, being the leading risk factor for type 2 diabetes
mellitus (T2DM) (3).
The term ‘diabesity’ describes the pathophysiologic link
between obesity and T2DM and was first introduced by
Sims et al (4) in 1973. In 2019, the International Diabetes
Federation estimated that 463 million individuals world
wide have diabetes, projecting that by 2045, there will be
>700 million cases (5). The presence of ‘diabesity’ enhances
the risk of developing cardiovascular disease, thus increasing
morbidity and mortality (6,7). Managing diabesity is chal
lenging, consideri ng that numerous fre quently used antidiabetic
agents, such as sulfonylureas, meglitinides, thiazolidinediones
and insulin, may lead to weight gain and therefore cause a
vicious cycle (8).
One of the most modern drug classes available that is able to
achieve both glycemic control and weight loss are glucagon‑like
peptide 1 (GLP‑1) receptor agonists (GLP‑1 RAs). GLP‑1 RAs
are widely used as a glucose‑lowering therapy with weight
reduction and cardiovascular benets in T2DM, having also
beneficial effects in non‑diabetic obesity as a weight loss
Future perspectives in diabesity treatment: Semaglutide,
a glucagon‑like peptide 1 receptor agonist (Review)
MARIANA CORNELIA TILINCA1,2, ROBERT AURELIAN TIUCA3,4,
CRISTINA NICULAS5, ANDREEA VARGA6,7 and IOAN TILEA1,7
1Department of Internal Medicine, ‘George Emil Palade’ University of Medicine, Pharmacy, Science and Technology of
Targu Mures, 540142 Targu Mures; 2Compartment of Diabetology, Emergency Clinical County Hospital, 540136 Targu Mures;
3Department of Endocrinology, ‘George Emil Palade’ University of Medicine, Pharmacy, Science and Technology of
Targu Mures, 540142 Targu Mures; 4Department of Endocrinology, Mures County Clinical Hospital, 540139 Targu Mures;
5Richter Pharmacy 7, 400129 Cluj Napoca; 6Department of Family Medicine, ‘George Emil Palade’ University of Medicine,
Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures; 7Department of Cardiology II,
Emergency Clinical County Hospital, 540042 Targu Mures, Romania
Received May 5, 2021; Accepted July 27, 2021
DOI: 10.3892/etm.2021.10601
Correspondence to: Dr Robert Aurelian Tiuca, Department of
Endocrinology, Mures County Clinical Hospital, 38 Gheorghe
Marinescu Street, 540139 Targu Mures, Romania
E‑mail: tiuca.robert@gmail.com
Key words: semaglutide, glucagon‑like peptide 1, type 2 diabetes
mellitus, obesity, diabesity
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
2
adjuvant therapy (9,10). The present narrative review aimed
to highlight the effects of semaglutide, the most recently
approved GLP‑1 RA for T2DM as indicated in the existing
literature, and to emphasize the emerging role of semaglutide
in managing diabesity and non‑diabetic obesity.
2. GLP‑1‑biological effects and development of GLP‑1 RAs
Biological effects. GLP‑1 is an incretin hormone secreted in
a biphasic pattern by the neuroendocrine L cells in the distal
ileum and colon after consumption of nutrients, particu
larly glucose and other carbohydrates (11,12). It has a short
elimination half‑life (1‑2 min) due to proteolysis by dipeptidyl
peptidase IV and renal elimination (12). GLP‑1 receptors
are expressed in numerous organs, mainly occurring in the
pancreas, central nervous system (hypothalamus) and the
gastrointestinal tract, but also in the heart and kidneys (12).
GLP‑1 stimulates insulin secretion from the β‑pancreatic cells
in a glucose‑dependent manner, also promoting β‑pancreatic
cell survival and proliferation (13,14). Furthermore, GLP‑1
reduces glucagon secretion by α‑pancreatic cells through
complex endocrine mechanisms, which include somatostatin
stimulation and insulinotropic effects on the β‑pancreatic
cells (12). By slowing down gastric emptying, GLP‑1 further
reduces blood glucose and appetite (15). This effect on appetite
is not only attributed to the delayed gastric emptying but also
to its inuence on the hypothalamus as a neurotransmitter,
particularly on the lateral hypothalamus, and the paraventric‑
ular and arcuate nucleus (16,17). Other effects of endogenous
GLP‑1 include reduction in systolic blood pressure, increased
myocardial contraction, improved endothelial vasodilation,
increased glycogen storage, improved lipid prole, diuresis
and natriuresis induction (18‑21).
Development of GLP‑1 RAs. At present, six injectable (subcu‑
taneous) GLP‑1 RAs and one oral formulation are available in
Europe for T2DM treatment. Based on their pharmacological
properties, GLP‑1 RAs are classied into short‑ or long‑acting
agents. Short‑acting GLP‑1 RAs include exenatide stan
dard‑release (Byetta) and lixisenatide (Lyxumia). Their major
mechanism of action is based on slowing gastric emptying
and lowering postprandial glucose. Long‑acting GLP‑1 RAs
include exenatide modified‑release (Bydureon), liraglutide
(Victoza), dulaglutide (Trulicity) and semaglutide (Ozempic).
Compared to short‑acting compounds, long‑acting agents have
a mechanism of action that mainly comprises stimulating
insulin secretion and inhibiting glucagon release, thus inu
encing both postprandial and fasting glucose. The posology of
GLP‑1 RAs in T2DM is illustrated in Table I (22,23).
Liraglutide was the rst antidiabetic treatment approved
as a weight reduction drug in non‑diabetic obesity. Sold under
the name of Saxenda, liraglutide at a dose of 3.0 mg once daily
was approved by both Food and Drug Administration in 2014
and the European Medicines Agency in 2015 for long‑term
weight management (24).
3. Semaglutide in diabesity and non‑diabetic obesity
Excess weight, particularly when associated with visceral fat,
increases the risk of insulin resistance, metabolic syndrome
and T2DM (25,26). The link between excess weight and T2DM
supposably lies in the inflammatory state associated with
excess adipose tissue. Several pro‑inammatory mediators,
such as tumor necrosis factor‑α, interleukin‑6 and complement
component 3, along with fatty‑acid lipotoxicity inhibit intra
cellular insulin signaling, which may lead to pancreatic βcell
dysfunction and subsequently to T2DM (27). When a new
diagnosis of T2DM is made, it is crucial to educate the patient
regarding the importance of a healthy lifestyle, which includes
avoiding excess calories (particularly high‑glycemic‑index
carbohydrates) and increasing physical activity to prevent
cardiovascular and metabolic complications. Nicola et al (28)
noted a signicantly higher low‑density lipoprotein cholesterol,
hypertriglyceridemia, low high‑density lipoprotein cholesterol
and a higher prevalence of micro‑ and macroalbuminuria in
hypertensive diabetic patients.
The American Diabetes Association recommends
metformin as the first‑line drug for T2DM therapy, if not
contraindicated (10). GLP‑1 RAs are known to lower blood
glucose by stimulating insulin production in the pancreatic
β‑cells and inhibiting glucagon release by the pancreatic
α‑cells, combined with slowing gastric emptying and reducing
appetite and food consumption (29). Therefore, given their
beneficial effects on glucose metabolism and weight loss
potential, GLP‑1 RAs are currently recommended as a
second‑line therapy in T2DM. Furthermore, their action of
increasing insulin production and lowering glucagon action is
tailored in a glucose‑dependent manner, thus posing a low risk
of hypoglycemia and making them one of the most effective
and safe options when a more intensive antidiabetic treatment
is required (30).
Semaglutide (Ozempic) is a long‑acting GLP‑1 RA and
its administration is once‑weekly subcutaneously at doses of
0.5 and 1.0 mg, with 0.25 mg/week being the initiation dose
for the rst 4 weeks. The safety and efcacy of semaglutide
was investigated in the Semaglutide Unabated Sustainability
in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial
program. A summary of the major results from the SUSTAIN
clinical program is provided in Table II.
Semaglutide as a blood glucose‑lowering agent. SUSTAIN‑1
was a phase IIIa clinical trial that compared the safety and
efcacy of semaglutide (0.5 and 1.0 mg) over the course of
30 weeks vs. placebo in patients with T2DM that had no prior
drug therapy, only diet and exercise interventions. Compared to
the placebo, both doses of semaglutide produced a signicant
reduction in glycated hemoglobin (HbA1c) [‑1.45% with sema‑
glutide 0.5 mg vs. ‑1.55% with semaglutide 1.0 mg vs. ‑0.2%
with placebo; the estimated treatment difference (ETD) for
semaglutide 0.5 mg vs. placebo was ‑1.43% and the ETD for
semaglutide 1.0 mg vs. placebo was ‑1.53%; P for both doses
of semaglutide vs. placebo <0.0001] (31).
The SUSTAIN‑2 clinical trial compared semaglutide
0.5 and 1.0 mg with sitagliptin 100 mg over the course of
56 weeks in patients with T2DM inadequately controlled
with metformin, thiazolidinediones or both. HbA1c reduction
was greater with both doses of semaglutide vs. sitagliptin
(‑1.3% with 0.5 mg semaglutide vs. ‑1.6% with 1.0 mg sema
glutide vs. ‑0.5% with 100 mg of sitagliptin; ETD ‑0.77% with
semaglutide 0.5 mg and ‑1.06% with semaglutide 1.0 mg;
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 3
P for both doses of semaglutide vs. sitagliptin <0.0001 for
non‑inferiority and superiority) (32). Semaglutide 1.0 mg was
compared with once‑weekly exenatide in the SUSTAIN‑3
clinical trial, which was performed over the course of
56 weeks on 813 adults with T2DM on previous oral antidia‑
betic agents. A reduction in HbA1c of 1.5% with semaglutide
and 0.9% with exenatide was noted (ETD, 0.62%; P<0.0001
for noninferiority and superiority for semaglutide vs. exenatide
once‑weekly) (33).
SUSTAIN‑4 assessed the safety and efficacy of sema
glutide compared to insulin glargine in patients with T2DM
inadequately controlled with metformin (with or without
sulfonylureas). At week 30, semaglutide at 0.5 and 1.0 mg
achieved greater HbA1c reductions than insulin glargine
(1.21 vs. 1.64 vs. 0.83%; ETD, ‑0.38% with semaglutide 0.5 mg
and ‑0.81% with semaglutide 1.0 mg with ETD; P<0.0001 for
ETD for both doses of semaglutide vs. insulin glargine) (34).
In the SUSTAIN‑5 clinical trial, semaglutide was inves
tigated as an add‑on vs. placebo in patients with T2DM on
basal insulin, with or without metformin. At week 30, HbA1c
exhibited a signicant reduction of 1.4 and 1.8% with sema
glutide 0.5 and 1.0 mg, respectively, vs. 0.1% with placebo
(P for both doses of semaglutide vs. placebo <0.0001) (35).
The SUSTAIN‑7 clinical trial proved the superiority of
0.5 and 1.0 mg semaglutide in improving the mean HbA1c
when compared to dulaglutide 0.75 and 1.5 mg. Semaglutide
0.5 mg reduced the mean HbA1c by 1.5 vs. 1.1% with dulaglu‑
tide 0.75 mg. Furthermore, 1.0 mg of semaglutide produced
a reduction of 1.8% in HbA1c vs. 1.4% with dulaglutide
1.5 mg (36).
SUSTAIN‑8 compared once‑weekly semaglutide 1.0 mg
with once‑daily canagliozin 300 mg in patients with T2DM
inadequately controlled with metformin. Semaglutide was
superior to canagliozin in reducing HbA1c (ETD, ‑0.49%;
P<0.0001) (37). In SUSTAIN‑9, the efficacy and safety of
semaglutide were assessed when added to a sodium glucose
cotransporter‑2 (SGLT‑2) inhibitor in patients with T2DM
with poor glycemic control. Semaglutide in addition to a
SGLT‑2 inhibitor signicantly reduced HbA1c (ETD, ‑1.42%;
P<0.0001) compared with placebo. Semaglutide added
to a SGLT‑2 inhibitor was well tolerated with significant
improvements in glycemic control (38).
In SUSTAIN‑10, semaglutide (1.0 mg/week) was compared
with liraglutide (1.2 mg/day) in subjects with T2DM treated
with 1‑3 oral antidiabetic drugs. A total of 577 subjects were
randomized to receive either semaglutide or liraglutide.
Patients receiving semaglutide had a superior reduction
in HbA1c (ETD, ‑0.69%; P<0.0001). Both treatments had
similar safety profiles, with semaglutide having a higher
frequency of gastrointestinal reactions compared to liraglutide
(43.9 vs. 38.3%) (39).
Semaglutide and body weight reduction benets. In SUSTAIN‑1,
a marked body weight loss was observed with both doses of
semag lutide when c o m p a r e d to pl a c e b o. Sp e c i c a ll y, wi t h se m a
glutide at 0.5 and 1.0 mg, a weight reduction of 3.73 and 4.53 kg
kg was achieved, respectively, while the placebo had an insig
nicant loss of 0.98 kg (ETD vs. placebo, ‑2.75 and ‑3.56 kg
with semaglutide 0.5 and 1.0 mg, respectively; P for both doses
of semaglutide vs. placebo <0.0001) (31). In SUSTAIN‑2,
at week 56, a weight loss of 4.3 kg with semaglutide 0.5 mg
and 6.1 kg with semaglutide 1.0 mg, and 1.9 kg with sitagliptin
100 mg was achieved (ETD, ‑2.35 kg with semaglutide 0.5 mg
and ‑4.20 kg with semaglutide 1.0 mg vs. sitagliptin; P for both
doses of semaglutide vs. sitagliptin <0.0001, with superiority of
sitagliptin) (32).
The SUSTAIN‑3 trial indicated that semaglutide‑treated
subjects achieved a greater weight reduction when compared
Table I. Posology of GLP‑1 RA in type 2 diabetes mellitus.
GLP‑1 RA Structure Posology
Exenatide standard‑release Exenatide‑4 derivative 5 µg twice daily for rst month, then increase to 10 µg twice daily, before
meals
Lixisenatide Exenatide‑4 derivative 10 µg once daily rst two weeks, then increase to 20 µg once daily,
before meals
Exenatide modied‑release Exenatide‑4 derivative 2 mg once weekly, with or without meals
Liraglutide Modied human GLP‑1 0.6 mg once daily for rst week, then increase to 1.2 mg once daily
(further increase up to 1.8 mg if poor glucose control), with or without
meals
Dulaglutide Modied human GLP‑1 0.75 mg once weekly in monotherapy (1.5 mg once weekly as add‑on
therapy), with or without meals
Semaglutide Modied human GLP‑1 0.25 mg once weekly for rst month, then increase to 0.5 mg once
weekly for at least one month (further increase up to 1 mg in case of
poor glycemic control), with or without meals
Semaglutide (oral) Modied human GLP‑1 3 mg once daily for one month, then increase to 7 mg once daily for at
least one month (further increase up to 14 mg in case of poor glycemic
control), before meals
GLP‑1 RA, glucagon‑like peptide 1 receptor agonist.
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
4
to exenatide‑treated subjects (‑5.6 vs. ‑1.9 kg; ETD ‑3.78 kg;
P<0.0001) (33). SUSTAIN‑4 compared semaglutide vs. insulin
glargine. Body weight loss was observed in semaglutide‑treated
subjects and at week 30, a loss of 3.5 kg with semaglutide 0.5 mg
and 5.2 kg with semaglutide 1.0 mg, compared to a weight gain
of 1.15 kg with insulin glargine was observed (34). This result
came with no surprise given the appetite‑reducing effects of
GLP‑1 and the anabolic effects of insulin. When added to basal
insulin, in patients with T2DM with or without metformin
treatment, semaglutide produced a signicant body weight
Table II. Summary of clinical trials from the SUSTAIN program.
Clinical trial Aim Main results
SUSTAIN‑1 To assess the safety and efcacy of Semaglutide 0.5 and 1.0 mg signicantly reduced HbA1c vs. placebo
semaglutide vs. placebo in T2DM (‑1.45 vs. ‑1.55 vs. ‑0.2%); semaglutide 0.5 and 1.0 mg signicantly
patients without prior drug therapy reduced body weight vs. placebo (‑3.73 vs. ‑4.53 vs. ‑0.98 kg)
SUSTAIN‑2 To assess the safety and efcacy of Semaglutide 0.5 and 1.0 mg achieved a greater HbA1c
semaglutide vs. sitagliptin in T2DM reduction vs. sitagliptin 100 mg (‑1.3 vs. ‑1.6 vs. ‑0.5%);
patients with poor control on semaglutide 0.5 and 1.0 mg achieved a greater body weight
metformin, thiazolidinediones or both reduction vs. sitagliptin 100 mg (‑4.3 vs. ‑6.1 vs. ‑1.9 kg)
SUSTAIN‑3 To assess the safety and efcacy of Semaglutide 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. once‑weekly exenatide exenatide once weekly 2.0 mg (‑1.5 vs. ‑0.9%); semaglutide 1.0 mg
in T2DM patients on previous oral achieved a greater body weight reduction vs. exenatide once weekly
antidiabetic agents 2.0 mg (‑5.6 vs. ‑1.9 kg)
SUSTAIN‑4 To assess the safety and efcacy of Semaglutide 0.5 and 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. insulin glargine in insulin glargine (‑1.21 vs. ‑1.64 vs. ‑0.83%); semaglutide 0.5 and 1.0 mg
T2DM patients with poor control on achieved a greater body weight reduction vs insulin glargine
metformin, with or without sulfonylureas (‑3.5 vs. ‑5.2 vs. +1.15 kg)
SUSTAIN‑5 To investigate the superiority of Semaglutide 0.5 and 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. placebo in T2DM placebo (‑1.4 vs. ‑1.8 vs. ‑0.1%); semaglutide 0.5 and 1.0 mg achieved
patients on basal insulin, with or without a greater body weight reduction vs. placebo (‑3.7 vs. ‑6.4 vs. ‑1.4 kg)
metformin
SUSTAIN‑6 To investigate the cardiovascular safety Semaglutide arm had a lower primary outcome (rst occurrence of
of semaglutide in T2DM cardiovascular death, nonfatal myocardial infarction or nonfatal
stroke) occurrence vs. placebo (6.6 vs. 8.9%); semaglutide arm had
lower rates of new or worsening nephropathy vs. placebo
(3.8 vs. 6.1%); semaglutide arm had a higher incidence of retinopathy
complications vs. placebo (3.0 vs. 1.8%)
SUSTAIN‑7 To assess the safety and efcacy of Semaglutide 0.5 mg achieved a greater HbA1c reduction vs.
semaglutide vs. dulaglutide in T2DM dulaglutide 0.75 mg (‑1.5 vs. ‑1.1%); semaglutide 1.0 mg achieved a
patients with poor control on metformin greater HbA1c reduction vs. dulaglutide 1.5 mg (‑1.8 vs. ‑1.4%);
semaglutide 0.5 mg achieved a greater weight reduction vs. dulaglutide
0.75 mg (‑4.6 vs. ‑2.3 kg); semaglutide 1.0 mg achieved a greater body
weight reduction vs. dulaglutide 1.5 mg (‑6.5 vs. ‑3.0 kg)
SUSTAIN‑8 To assess the safety and efcacy of Semaglutide 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. canagliozin in T2DM canagliozin 300 mg (‑1.5 vs. ‑1.0%); semaglutide 1.0 mg achieved a
patients with poor control on metformin greater body weight reduction vs. canagliozin 300 mg
(‑5.3 vs. ‑4.2 kg)
SUSTAIN‑9 To assess the safety and efcacy of Semaglutide markedly reduced HbA1c when added to a SGLT‑2
semaglutide when added to a SGLT‑2 inhibitor vs. placebo (‑1.5 vs. ‑0.1%); semaglutide markedly reduced
inhibitor in patients with poorly body weight when added to a SGLT‑2 inhibitor vs. placebo
controlled T2DM (‑4.7 vs. ‑0.9 kg)
SUSTAIN‑10 To assess the safety and efcacy of Semaglutide 1.0 mg had a greater HbA1c reduction vs. liraglutide
semaglutide vs. liraglutide in T2DM 1.2 mg (‑1.7 vs. ‑1.0%); semaglutide 1.0 mg had a greater body weight
patients on 1‑3 oral antidiabetic agents reduction vs. liraglutide 1.2 mg (‑5.8 vs. ‑1.9 kg)
T2DM, type 2 diabetes mellitus; HbA1c, glycated hemoglobin; SUSTAIN, Semaglutide Unabated Sustainability in Treatment of Type 2
Diabetes.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 5
reduction vs. placebo according to the results of SUSTAIN‑5
(‑3.7 kg with semaglutide 0.5 mg vs. ‑6.4 kg with semaglutide
1.0 mg vs. ‑1.4 kg with placebo; P for both doses of sema
glutide vs. placebo <0.0001) (35). In SUSTAIN‑7, semaglutide
was superior to dulaglutide regarding body weight reduction
properties. Semaglutide 0.5 mg achieved a weight reduction of
4.6 vs. 2.3 kg with dulaglutide 0.75 mg. Furthermore, an even
greater difference was observed between semaglutide 1.0 mg
vs. dulaglutide 1.5 mg (‑6.5 vs. ‑3.0 kg) (36).
Semaglutide was superior to canagliflozin in reducing
body weight (ETD, ‑1.06 kg; P<0.0029) in SUSTAIN‑8 (37).
A sub‑study of SUSTAIN‑8 compared the effects of sema
glutide 1.0 mg and once‑daily canagliozin 300 mg on body
composition in individuals with T2DM uncontrolled with
metformin. The results indicated no signicant differences
between semaglutide and canagliozin regarding changes in
body composition (40). In SUSTAIN‑9, adding semaglutide
to a SGLT‑2 inhibitor achieved signicant improvements in
body weight reduction compared to placebo (ETD, ‑3.81 kg;
P<0.0001) (38). Given the positive outcomes that were obtained
when adding semaglutide to canagliozin, it is indicated that
combining a GLP‑1 RA and a SGLT‑2 inhibitor may provide
an additive effect in improving glycemic control and body
weight reduction and also in reducing cardiovascular risk and
renal impairment.
Patients receiving semaglutide in SUSTAIN‑10 had
a superior reduction in body weight compared with the
liraglutide‑treated group (ETD, ‑3.83 kg; P<0.0001) (39).
Semaglutide was studied as a possible chronic weight
management drug in non‑diabetic obesity. A randomized,
double‑blinded, placebo‑controlled trial performed on
957 individuals without diabetes was performed to evaluate
the safety and efcacy of semaglutide in comparison with
liraglutide and placebo in promoting weight loss. Participants
received semaglutide at dosages ranging from 0.05 to 0.4 mg
or liraglutide 3.0 mg as once‑daily subcutaneous injections.
The estimated mean loss for the 0.4 mg semaglutide group
was ‑13.8 vs. ‑2.3% with placebo. Mean body weight reduc
tions with ≥0.2 mg semaglutide vs. liraglutide were signicant
(‑13.8 to ‑11.2 vs. ‑7.8%) (41). A double‑blinded randomized
clinical trial, which included 1,961 adults without T2DM with
a body mass index of at least 30 or at least 27 kg/m2 with
≥1 weight‑related coexisting comorbidity, investigated the role
of 2.4 mg subcutaneous semaglutide vs. placebo in addition
to lifestyle interventions. At week 68, the mean body weight
change was highly signicant in the semaglutide group vs.
the placebo group (‑14.9 vs. ‑2.4%; ETD, ‑12.4%; P<0.001).
A weight reduction of at least 5% was achieved by 86.4% of
the subjects in the semaglutide group vs. 31.5% in the placebo
group. A 10% weight reduction was achieved by 69.1% of
subjects in the semaglutide group vs. 12.0% of subjects in
the placebo group. A 15% weight reduction occurred in
50.5% of patients of the semaglutide group vs. 4.9% in the
placebo group (42). Given the proven benets of semaglutide
in managing chronic excess weight and its good safety prole,
the Food and Drug Administration recently approved the use
of semaglutide 2.4 mg/once‑weekly as an add‑on‑therapy to
lifestyle modications in adults with obesity or overweight
with at least one weight‑related comorbidity (43). Therefore,
semaglutide became the second GLP‑1 RA besides liraglutide
that may be used in managing non‑diabetic excess weight. The
Food and Drug Administration approval was based on the
results from the Semaglutide Treatment Effect in People with
Obesity (STEP) program, which consisted of four phase III
clinical trials. A summary of the STEP program is illustrated
in Table III (42,44‑46).
Oral semaglutide: Blood glucose and body weight benets.
Oral semaglutide (Rybelsus), the first oral GLP‑1 RA,
was studied in 10 phase IIIa clinical trials as part of the
PIONEER program. PIONEER‑1 was a 26‑week randomized,
double‑blinded clinical trial that compared the efcacy and
safety of oral semaglutide (3, 7 or 14 mg) as monotherapy
with placebo in subjects with T2DM managed by lifestyle
interventions. It was demonstrated that oral semaglutide at
all doses was superior to the placebo in improving HbA1c
(ranging from ‑0.6 to ‑1.1%) and in body weight reduction
(14 mg dose) (47). Results from PIONEER‑2 suggested that
oral semaglutide 14 mg was superior in reducing HbA1c
compared with empagliflozin 25 mg in a 52‑week trial
(1.3 vs. 0.9%; ETD ‑0.4%; P<0.0001). Furthermore, at week 52,
oral semaglutide achieved an average weight reduction of
4.7 vs. 3.8 kg with empagliozin, rendering oral semaglutide
signicantly more effective (P=0.0114) (48). The PIONEER‑4
clinical trial demonstrated that oral semaglutide (14 mg) was
non‑inferior in decreasing HbA1c to subcutaneous liraglutide
(1.8 mg) at week 26 (ETD, ‑0.1%; P<0.0001) and superior to
placebo (ETD, ‑1.1%; P<0.0001). Furthermore, oral semaglu
tide achieved a greater weight reduction than liraglutide and
placebo (‑4.4 vs. ‑3.1 vs. 0.5 kg; ETD, ‑1.2 kg vs. liraglutide
and ‑3.8 kg vs. placebo; P=0.0003 and P<0.0001, respec
tively) (49).
The PIONEER 10 clinical trial investigated the efcacy and
safety of oral semaglutide vs. dulaglutide in Japanese patients
with uncontrolled T2DM. Oral once‑daily semaglutide (14 mg)
achieved a signicant HbA1c reduction vs. once‑weekly dula
glutide (0.75 mg) (ETD, ‑0.3%; P=0.0170). Furthermore, oral
semaglutide signicantly reduced body weight vs. dulaglutide
(ETD, ‑2.6 kg for oral semaglutide 14 vs. 0.75 mg dulaglutide;
P<0.0 0 01) (50).
Cardiovascular benets of semaglutide. The SUSTAIN‑6 clin
ical trial investigated the cardiovascular safety of once‑weekly
subcutaneous administration of semaglutide. The primary
outcome composite (rst occurrence of cardiovascular death,
nonfatal myocardial infarction or nonfatal stroke) occurred in
6.6% in the semaglutide group vs. 8.9% in the placebo group
(P<0.0001 for noninferiority). Mortality rates from cardiovas‑
cular causes were similar among the studied groups, while
the semaglutide group had an advantage regarding lower rates
of new or worsening nephropathy [3.8 vs. 6.1%, hazard ratio
(HR)=0.64, P<0.01] (51). Furthermore, by improving glucose
metabolism, GLP‑1 RAs are able to prevent the development of
macroalbuminuria and also maintain an adequate glomerular
ltration rate, and are an efcient and safe option in diabetic
nephropathy (52). However, semaglutide‑treated subjects had
a higher incidence of retinopathy complications vs. placebo
(P=0.02) (51). Recently published results demonstrated that
semaglutide improved health‑related quality of life vs. placebo
in patients with T2DM with high cardiovascular risk in the
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
6
SUSTAIN‑6 trial, possibly explained by the reduction of
HbA1c and weight loss (53).
PIONEER‑6 investigated the cardiovascular outcomes for
oral semaglutide in subjects with T2DM and with high cardio‑
vascular risk in an event‑driven, randomized, double‑blinded,
placebo‑controlled trial. Oral semaglutide was non‑inferior to
placebo regarding cardiovascular safety, with major cardiovas‑
cular events occurring in 3.8% of the oral semaglutide‑treated
subjects vs. 4.8% in the placebo group (HR=0.79; P<0.001
for non‑inferiority) (54). The study did not have the statistical
power to demonstrate superiority, as it was an event‑driven
trial. Death from cardiovascular causes occurred in 0.9%
in the oral semaglutide group vs. 1.9% in the placebo group
(HR=0.49) and nonfatal myocardial infarction occurred in
2.3% in the oral semaglutide group vs. 1.9% in the placebo
group (HR=1.18), while nonfatal stroke occurred in 0.8% in
the oral semaglutide group vs. 1.0% in the placebo group
(HR=0.74). All‑cause mortality was encountered in 1.4% in
the oral semaglutide group vs. 2.8% in the placebo group
(HR=0.51) (54).
Semaglutide and nonalcoholic fatty liver disease (NAFLD).
NAFLD is a metabolic liver disease that has a broad spectrum
of clinical presentation, ranging from simple steatosis to severe
forms such as nonalcoholic steatohepatitis (NASH), cirrhosis
and hepatocellular carcinoma (55). Similar to that of T2DM
and obesity, the incidence of NAFLD is increasing worldwide.
It is estimated that up to 70‑80% of patients with T2DM and/or
obesity present with NAFLD (56,57). T2DM is an important
risk factor for the progression of NAFLD to more severe
forms (58‑60). The exact pathophysiological mechanisms
which lead to NAFLD remain to be completely elucidated,
but several proposed hypotheses include insulin resistance,
environmental factors, polymorphisms, adipose tissue
expandability and spleen mechanisms to promote liver fat
accumulation (61). Currently, lifestyle changes are the primary
tool in managing NAFLD, as to date, no pharmacological
treatment has been approved.
GLP‑1 RAs may be a potential therapeutic option given
their benets in T2DM and obesity, the two major drivers of
NAFLD (62). In a systematic review published in 2020 by
Lv et al (63), GLP‑1 RAs were determined to improve liver
enzymes and hepatic steatosis. A recently published meta
nalysis by Mantovani et al (64) investigated the published
data of placebo‑controlled, active‑controlled or randomized
controlled trials that evaluated the efficacy and safety of
GLP‑1 RAs in treating NAFLD or NASH in adults with or
without T2DM. They revealed GLP‑1 RAs to be efcient in
Table III. Summary of clinical trials from the STEP program.
Clinical trial Design Aim Main results
STEP‑1 68‑week randomized, To investigate the efcacy and safety of Semaglutide 2.4 mg achieved a weight
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. loss of 14.9 vs. 2.4% with placebo;
placebo‑controlled placebo in 1,961 adults with obesity or 86.4% of the semaglutide 2.4 mg group
overweight with comorbidities achieved a weight loss of ≥5 vs. 31.5%
with placebo
STEP‑2 68‑week randomized, To compare the efcacy and safety of Semaglutide 2.4 mg achieved a
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. weight loss of 9.6 vs. 7.0% with
placebo‑controlled semaglutide 1.0 mg/once‑weekly vs. semaglutide 1.0 mg vs. 3.4% with
placebo in 1,210 adults with T2DM and placebo; 68.8% of semaglutide
obesity or overweight with comorbidities 2.4 mg group achieved a weight loss
of ≥5 vs. 28.5% with placebo
STEP‑3 68‑week randomized, To investigate the efcacy and safety of Semaglutide 2.4 mg achieved a
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. weight loss of 16.0 vs. 5.7% with
placebo‑controlled placebo in combination with intensive placebo; 86.6% of semaglutide
behavioral treatment in 611 adults with 2.4 mg group achieved a weight loss
obesity or overweight with comorbidities of ≥5 vs. 47.6% with placebo
STEP‑4 68‑week randomized, To investigate the efcacy and safety of After 20 weeks run‑in, 803 adults
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. reached the target dose of semaglutide
placebo‑controlled placebo in 902 adults with obesity or 2.4 mg and were randomized to
overweight continued treatment or placebo for
48 weeks; after 48 weeks, semaglutide
2.4 mg achieved an additional weight
loss of 7.9 vs. 6.9% with placebo; after
68 weeks, semaglutide 2.4 mg achieved
a total weight loss of 17.4%
T2DM, type 2 diabetes mellitus; STEP, Semaglutide Treatment Effect in People with Obesity.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 7
improving NAFLD, particularly liraglutide and semaglutide. A
randomized, double‑blinded, placebo‑controlled, phase 2 trial
compared daily semaglutide (0.1, 0.2 and 0.4 mg) with placebo
in patients with biopsy‑conrmed NASH. NASH resolution
without worsening of brosis was observed in 40% of cases in
the semaglutide 0.1 mg group, in 36% of cases in the semaglu‑
tide 0.2 mg group and in 59% in the semaglutide 0.4 mg group,
compared with 17% of cases in the placebo group (P<0.001,
semaglutide 0.4 mg vs. placebo). However, there was no
signicant improvement regarding the brosis stage between
semaglutide 0.4 mg and the placebo (P=0.48) (65).
4. Semaglutide‑side effects and cautions
Semaglutide mainly shares the classically observed side
effects of other GLP‑1 RAs (Fig. 1).
Gastrointestinal side effects. The common side effects associ‑
ated with GLP‑1 RAs use are gastrointestinal reactions, mainly
nausea, vomiting and diarrhea. During the SUSTAIN program
that assessed safety parameters, the rate of discontinuation due
to adverse events was low (5‑13%), with SUSTAIN‑6 reporting
a higher discontinuation rate (almost 20%). The major
reasons for the discontinuation were gastrointestinal adverse
events (31‑36). Nausea occurred in 17.0%, diarrhea in 12.2%
and vomiting in 6.4% of patients treated with semaglutide
0.5 mg. As for patients treated with semaglutide 1.0 mg, nausea
occurred in 19.9%, diarrhea in 13.3% and vomiting in 8.4% of
cases (66,67). Semaglutide has a similar gastrointestinal safety
prole as other GLP‑1 Ras (68,69). A metanalysis from 2018
that included nine phase III randomized controlled trials and
9,773 subjects highlighted that semaglutide did not increase the
risk of any adverse events, hypoglycemia or pancreatitis, but
had a higher risk of gastrointestinal reactions (mainly nausea,
vomiting, diarrhea, abdominal discomfort and decreased appe‑
tite) when compared to other therapies [relative risk (RR)=1.98;
P<0.001] (70). Given that the occurrence of gastrointestinal
reactions is the main reason for treatment discontinuation, a
titration regimen is recommended for semaglutide, starting
with 0.25 mg once‑weekly for 4 weeks, increasing the dose
to 0.5 mg once‑weekly for at least 4 weeks. If a higher dose is
required to achieve proper glycemic control, the dose may then
be increased to 1.0 mg once‑weekly, assuming the tolerance
is adequate. For oral semaglutide, the initial dose is 3 mg/day
for the first month, then the dose should be increased to
7 mg/day for at least another month (the dose may be increased
up to 14 mg/day in the case of poor glycemic control).
Risk of hypoglycemia. The frequency of hypoglycemia was
observed to be usually low (1‑2%) when semaglutide was
not combined with insulin or sulphonylureas (31,32,36,71).
However, when added to sulphonylureas or insulin, hypogly
cemia had higher frequencies (4‑10%) (33‑35,71). Shi et al (70)
observed no increased risk of hypoglycemia with semaglutide
when compared to other therapies (RR=1.07; P=0.317).
Medullary thyroid carcinoma and pancreatitis concerns.
Rodent studies have indicated an increased risk of devel
oping medullary thyroid carcinoma following treatment
with GLP‑1 RAs, but without existing conrmation of these
results in humans (72,73). The SUSTAIN program suggested
no elevation in calcitonin levels. However, GLP‑1 RAs should
Figure 1. Side effects, cautions and concerns related to GLP‑1 RAs. GLP‑1 RAs, glucagon‑like peptide 1 receptor agonists.
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
8
not be used in individuals with a personal or family history of
medullary thyroid carcinoma or multiple endocrine neoplasia
type 2A and 2B (23,74). Concerns about pancreatitis in
incretin‑based therapy have been raised due to mild elevations
in amylase and/or lipase levels (75). The risk of pancreatitis
with semaglutide was not signicantly higher when compared
with other therapies (0.3 vs. 0.4%, RR=0.82; P=0.641) (70).
In 2020, Abd El Aziz et al (76) published a metanalysis based
on cardiovascular outcome trials and indicated no signicant
risk of acute pancreatitis or any malignant disease.
Ocular and renal effects. SUSTAIN‑6 noted an increased
risk of retinopathy complications (vitreous hemorrhage,
blindness or conditions requiring treatment with an intra
vitreal agent or photocoagulation) in the semaglutide group
vs. the placebo group (3.0 vs. 1.8%, HR=1.76, P=0.02) (51).
On the contrary, SUSTAIN‑1‑5 and ‑7 did not report any
similar results. One explanation for these observations may
be the HbA1c levels at baseline and the rapidity of reduction
of HbA1c, considering that rapid improvement in glucose
control has been associated with aggravated diabetic reti
nopathy (77‑79). No dose adjustment is required based on age
or in patients with mild, moderate or severe renal or hepatic
impairment; however, it is not recommended in patients with
end‑stage kidney disease and experience in severe hepatic
disease is limited (66,67).
5. Future considerations
Weight loss induced by GLP‑1 RAs is usually observed after
long‑term treatment. GLP‑1 RAs promote weight loss mainly
by reducing appetite, thus reducing food consumption and
by increasing satiety. Treatment adherence is important,
as well as lifestyle changes, which include dietary caloric
decit and increased physical activity. It was observed that
a higher dose of GLP‑1 RA is associated with a higher
chance to obtain a higher weight reduction. However, weight
reduction usually lasts as long as the treatment is continued,
with near‑baseline weight values returning within months of
discontinuation of pharmacological treatment as reported by
Kelly et al (80).
Semaglutide is the second GLP‑1 RA that may be safely
and efciently used in non‑diabetic individuals with excess
weight, providing a new milestone in the pharmacological
treatment of obesity. Furthermore, oral semaglutide, given
its posology, may provide higher attractiveness and better
treatment adherence, and thus, future research into the use of
oral semaglutide in non‑diabetic obese patients may provide
novel insight and an effective and safe weight‑loss method.
Combination therapy with semaglutide is also being studied.
A randomized, placebo‑controlled, multiple ascending dose,
phase Ib trial investigated the combination of semaglutide
2.4 mg with cagrilintide, a long‑acting amylin analogue.
Concomitant treatment with cagrilintide and semaglutide
was well tolerated and produced a greater weight loss than
semaglutide alone (81). Further studies are required to assess
variable combination options with semaglutide to provide
novel treatments for long‑term weight management.
The cardiovascular safety of semaglutide was assessed
in SUSTAIN‑6 for once‑weekly subcutaneous formulation
and in PIONEER‑6 for the oral formulation, as discussed
previously. A Heart Disease Study of Semaglutide in Patients
with Type 2 Diabetes (SOUL) will bring additional data
regarding the cardiovascular outcomes with oral semaglutide
vs. placebo (82,83). Semaglutide, as with other agents from
the GLP‑1 RAs drug class, reduces the risk of cardiovas
cular events in high‑risk patients. The American Diabetes
Association currently recommends the use of GLP‑1 RAs as
part of the antidiabetic treatment in patients with T2DM with
atherosclerotic cardiovascular disease or established kidney
disease (10). The positive effects of GLP‑1 RAs on cardiovas‑
cular function may be explained by the benecial effects of
this drug class on glucose metabolism, body weight and blood
pressure. The exact mechanisms of how GLP‑1 RAs provide
cardiovascular benefits remain to be elucidated in future
research. Furthermore, long‑term studies are required to inves‑
tigate the potential additive effects on the cardiovascular and
renal function of the combination between a GLP‑1 RA and an
SG LT‑2 i n h ibi tor.
Semaglutide achieved promising results in improving
NAFLD. Larger randomized clinical trials are required to
conrm its applicability in NAFLD. Furthermore, clinicians
should focus on preventing the development of NAFLD by
promoting a healthy lifestyle, particularly in individuals
suffering from T2DM and obesity who are at high risk of
developing steatohepatitis.
6. Conclusions
The present review highlighted the benets of semaglutide not
only as an antidiabetic agent but also as a drug with effective
weight reduction properties. Clinicians should be aware that
semaglutide therapy is one of the most modern methods of
treatment for patients with T2DM and obesity, and has recently
been approved for the treatment of non‑diabetic excess weight.
Semaglutide (both subcutaneous and oral formulation) is an
efcient and safe therapeutic approach for diabesity, with an
excellent cardiovascular prole. Regarding the microvascular
complications, potential for reducing diabetic nephropathy
was noted, with concerns regarding a possible worsening of
diabetic retinopathy, thus requiring further studies for clari
cation. The perspective of oral semaglutide as an antiobesity
drug is promising and may be associated with increased treat‑
ment adherence. There is still increased potential for further
research to enhance and optimize the use of semaglutide in
diabesity and non‑diabetic obesity to reduce morbidity and
mortality associated with these metabolic disorders and to
improve quality of life.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
Not applicable.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 9
Authors' contributions
MCT and RAT contributed to the design and conception of
the study. RAT and CN searched and consulted the relevant
literature, selected the studies/data and wrote the rst draft of
the manuscript. MCT, AV and IT substantially added contribu‑
tions by revising and editing the nal manuscript. All authors
have read and approved the nal version of the manuscript.
Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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... Exenatide treatment resulted in an average HbA1c reduction of 0.73% compared to placebo, with 32.5% of exenatide-treated patients achieving an HbA1c level of less than 7.0%, compared to only 7.4% in the placebo group. Body weight was reduced by an average of 1.5 kg with exenatide compared to placebo [144]. ...
... Patients who made the switch experienced additional A1C reductions of approximately 0.5% (mean A1C change from baseline was −1.4% at week 52) and sustained reductions in fasting plasma glucose levels from weeks 28 to 52. Patients who continued on exenatide QWS-AI therapy for 52 weeks maintained their A1C levels and weight loss without any additional safety or tolerability issues [144]. ...
... In conclusion, this study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well-tolerated [142][143][144]. The main outcomes and side effects observed in clinical trials of GLP1-RA against obesity are summarized in Table 5. Exenatide once weekly induced nausea and diarrhea [146] Duration-5 ...
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Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.
... This aspect is important, given the ever-increasing global prevalence of obesity and type 2 diabetes mellitus (T2DM). With their spread, obesity and T2DM pose major economic and health burdens [3]. In 2016, the World Health Organization estimated that more than 650 million adults worldwide were obese [4]. ...
... In 2016, the World Health Organization estimated that more than 650 million adults worldwide were obese [4]. In 2019, the International Diabetes Federation estimated that 463 million people worldwide have diabetes and predicted > 700 million cases by 2045 [3,5]. These two diseases often occur together, and the term "diabesity" describes the pathophysiological link between them. ...
... These two diseases often occur together, and the term "diabesity" describes the pathophysiological link between them. The presence of diabesity increases the risk of developing cardiovascular disease, morbidity, and mortality [3]. ...
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... Consequently, there is a need for a practical, efficient and secure therapy for obesity and associated metabolic disorders in order to reduce mortality and improve quality of life [70]. Since several commonly used antidiabetic drugs, including sulfonylureas and insulin, may cause weight gain and so create a vicious circle, managing "diabesity" can be difficult [71]. A highly effective class of medicaments for type 2 DM is represented by the Glucagon-Like Peptide-1 (GLP-1) receptor agonist (RA) [8]. ...
... Exenatide, the first GLP-1 RA received approval in June 2005. Since then there are several other injectable agents available in the treatment of DM and obesity such as the shortacting formulation lixisenatide and exenatide and the longer-acting-formulation liraglutide, once-weekly extended-release dulaglutide, semaglutide and exenatide [21,71]. Tirzepatide is a novel and the first dual association between a GLP-1 and a Glucose-dependent Insulinotropic Peptide (GIP) RA recommended in obese patients, administered subcutaneously once weekly, which provides consistent and persistent reductions in body weight [25]. ...
... Type 2 diabetes (T2D) and obesity are major public health burdens with an important economic impact and their incidences have increased in the past decades. 1,2 It is estimated that approximately 537 million adults around the world affected with diabetes in 2021, 3 and this number is expected to increase to over 700 million by 2045. 4 T2D is the most prevalent type of diabetes, accounting for about 90% of the population suffering from diabetes. 5,6 Patients with T2D are at high risk for long-term macrovascular and microvascular complications including cardiovascular diseases. ...
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Purpose The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use. Methodology The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies. Results Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug–drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this. Conclusion This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.
... In a recent analysis of ADJUNCT ONE and ADJUNCT TWO, two randomized controlled phase 3 trials in T1DM, treatment with daily liraglutide 1.8 mg over 52 weeks was associated with a significant reduction in the placebo-adjusted HbA1c, body weight, and insulin dose (ADJUNCT ONE: −0.30%, −5.0 kg, and −12%; ADJUNCT TWO: −0.35%, −4.8 kg, and −10%, respectively) [6]. In a large retrospective cohort study of 1,822 patients with T1DM treated with predominantly short-acting GLP-1RAs, we have recently shown a clinically meaningful reduction in HbA1c, but with limited weight loss and cardiorenal benefits [11,12]. A recent study of patients with T1DM receiving low-dose semaglutide 0.5 mg weekly has shown improvement in weight and reduction in basal/bolus insulin [13]. ...
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The efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RA) in type 2 diabetes mellitus is well-established. GLP1-RAs are not approved for use in type 1 diabetes mellitus (T1DM). A 34-year-old woman with a 23-year history of T1DM presented for review for weight gain (weight 63 kg, BMI 26.9 kg/m²) and increased HbA1c (8.3%) and glycemic variability. Subcutaneous semaglutide (1 mg weekly) was commenced. After two months, there was decrease in weight by 12 kg, body fat percent by 15%, visceral fat by 7%, and a reduction in insulin dose, glycemic variability, and HbA1c. Semaglutide could be an important adjunct to insulin treatment in T1DM.
... It promotes the release of insulin from pancreatic β-cells in response to glucose while inhibiting glucagon secretion from pancreatic α-cells. Furthermore, GLP-1 slows stomach emptying and helps convey feelings of fullness in the central nervous system (Scheen, 2018;Tilinca et al., 2021). The GLP-1 receptor (GLP-1R) is widely distributed in the cardiovascular system. ...
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... For obesity-related cardiovascular and cerebrovascular diseases, diabetic nephropathy, metabolic liver disease, and polycystic ovary syndrome, semaglutide also has advantages. Since semaglutide is a long-acting agonist of the GLP-1 receptor, it can be injected subcutaneously just once a week, making continuous use of the drug more convenient and improving adherence to treatment for patients [30][31][32][33][34][35][36][37][38][39][40][41] . Considering the significant metabolic benefits and reliable safety profiles of agents, adjunctive treatment with semaglutide in postbariatric surgery patients may produce better metabolic outcomes. ...
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... The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) program, comprising 10 clinical trials that compared semaglutide to a placebo or other antidiabetic treatments, provided evidence for the effectiveness of injectable semaglutide as a monotherapy or an add-on therapy [10]. A reduction in HbA1c up to 1.5-1.8%, a reduction in major adverse cardiovascular (MACE) events rates, kidney prevention, and weight loss after the semaglutide treatment were reported [11][12][13][14][15], as well as an overall favorable risk/benefit profile [7]. ...
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Background: Semaglutide is a recently approved glucagon-like peptide-1 receptor agonist. Several trials reported the protective effect of injectable semaglutide on cardiovascular (CV) risk by reducing major adverse cardiovascular events in type 2 diabetes patients. Strong preclinical evidence supports the CV benefits of semaglutide through an effect on atherosclerosis. However, scant evidence is available about the protective mechanisms of semaglutide in clinical practice. Methods: A retrospective observational study was conducted among consecutive type 2 diabetes patients treated with injectable semaglutide in Italy between November 2019 and January 2021 when the drug was first available in the country. The primary aims were the assessment of the carotid intima-media thickness (cIMT) and hemoglobin A1c (HbA1c) levels. The secondary aims were the evaluation of anthropometric, glycemic, and hepatic parameters and plasma lipids, including the assessment of the triglyceride/high-density lipoprotein ratio as an indirect marker of atherogenic small, dense low-density lipoprotein particles. Results: Injectable semaglutide reduced HbA1c and cIMT. An improvement in CV risk factors and the triglyceride/high-density lipoprotein ratio was reported. Moreover, through correlation analyses, we found that hepatic fibrosis and steatosis indices and the anthropometric, hepatic, and glycemic parameters, as well as plasma lipids, were unrelated to the variations in cIMT and HbA1c. Conclusions: Our findings suggest the effect of injectable semaglutide on atherosclerosis as a key CV protective mechanism. Considering the favorable effects on atherogenic lipoproteins and hepatic steatosis indices, our results support the pleiotropic effect of semaglutide beyond glycemic control.
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Background Semaglutide, a glucagon‐like peptide‐1 receptor agonist, has been utilized for the treatment of type 2 diabetes. Recently, it has gained popularity for its ability to aid in weight loss. However, rapid weight loss induced by semaglutide has been shown to lead to noticeable facial volume loss and the appearance of a prematurely aged face referred to as “Ozempic face.” As this term gains more popularity and increasingly more nondiabetic patients seek rapid weight loss options, there is growing concern among patients and healthcare providers regarding using semaglutide for weight loss as it may have a negative impact on facial esthetics. Objective The purpose of this paper is to investigate the semaglutide face phenomenon associated with GLP‐1 agonist use for the treatment of obesity. Methods A comprehensive search on PubMed was conducted to identify the available information related to semaglutide regarding Ozempic face. The search was conducted using a combination of keywords, including “semaglutide,” “semaglutide face,” and “Ozempic face.” Results “Semaglutide face” is recognized as having similar characteristics to a naturally occurring aging face. However, the characteristics of an Ozempic face occur in people much younger than what is seen with the natural aging process. While some believe that this phenomenon is attributed to acute weight loss at a faster rate than normal, many physicians argue that the semaglutide face phenomenon is more likely to occur with the amount of weight lost overall rather than whether that individual used a semaglutide medication to achieve the weight reduction or not. Overall, the semaglutide face phenomenon is characterized by elastin and collagen loss, fat and muscle volume loss, and excessive sagging skin. Conclusions The semaglutide face phenomenon highlights the esthetic implications of using semaglutide for the promotion of accelerated weight loss. While this term is not medically recognized, the hollow or sunken look following rapid weight loss sheds light on the effect of semaglutide in facial fat redistribution and volume loss. The metabolic changes induced by GLP‐1 agonists can impact adipose and muscle tissue, which can lead to changes in facial contour and overall appearance. While semaglutide‐induced facial changes may resemble signs of premature aging, they are distinct in their rapid onset and association with significant weight loss. Individuals experiencing semaglutide face have treatment options available depending on their own treatment goals.
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To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] <1.8), there were fewer first major adverse CV events with semaglutide vs. placebo, with HRs of 0.74 (95% CI 0.58–0.95) and 0.79 (0.57–1.11), respectively. In SUSTAIN 6, the results were significant for noninferiority and superiority, although the latter was not prespecified. Surprisingly, CV and all-cause mortality were significantly reduced by oral semaglutide in PIONEER 6. The ongoing SOUL CVOT will further inform about CV outcomes with oral semaglutide vs. placebo (NCT03914326). Findings from SUSTAIN 6 and PIONEER 6 fall within the spectrum reported with other GLP-1RA CVOTs: noninferiority vs. placebo for major CV events was seen with lixisenatide and exenatide extended-release, while superiority was demonstrated with liraglutide, albiglutide, and dulaglutide. Beneficial outcomes have been recognized in international guidelines, which recommend subcutaneous liraglutide, semaglutide, and dulaglutide to reduce the risk of CV events in high-risk patients. Both indirect mechanisms via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.
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Importance The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. Design, Setting, and Participants Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main Outcomes and Measures The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was −7.9% vs +6.9% with the switch to placebo (difference, −14.8 [95% CI, −16.0 to −13.5] percentage points; P < .001). Waist circumference (−9.7 cm [95% CI, −10.9 to −8.5 cm]), systolic blood pressure (−3.9 mm Hg [95% CI, −5.8 to −2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). Conclusions and Relevance Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial Registration ClinicalTrials.gov Identifier: NCT03548987
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Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are attractive options for the treatment of type 2 diabetes (T2D) because they effectively lower A1C and weight while having a low risk of hypoglycemia. Some also have documented cardiovascular benefit. The GLP-1 RA class has grown in the last decade, with several agents available for use in the United States and Europe. Since the efficacy and tolerability, dosing frequency, administration requirements, and cost may vary between agents within the class, each agent may offer unique advantages and disadvantages. Through a review of phase III clinical trials studying dulaglutide, exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, semaglutide, and oral semaglutide, 14 head-to-head trials were identified that evaluated the safety and efficacy of GLP-1 RA active comparators. The purpose of this review is to provide an analysis of these trials. The GLP-1 RA head-to-head clinical studies have demonstrated that all GLP-1 RA agents are effective therapeutic options at reducing A1C. However, differences exist in terms of magnitude of effect on A1C and weight as well as frequency of adverse effects.
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Importance Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches. Objective To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity. Design, Setting, and Participants Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30). Interventions Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks. Main Outcomes and Measures The co–primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight. Results Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was –16.0% for semaglutide vs –5.7% for placebo (difference, −10.3 percentage points [95% CI, −12.0 to −8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants. Conclusions and Relevance Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings. Trial Registration ClinicalTrials.gov Identifier: NCT03611582
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To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: −3.92%, 95% confidence intervals (CI) −6.27% to −1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52–6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.
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Background GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.
Article
Background: Cagrilintide, a long-acting amylin analogue, and semaglutide 2·4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination. Methods: In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18-55 years with a body-mass index 27·0-39·9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0·16, 0·30, 0·60, 1·2, 2·4, or 4·5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2·4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC0-168 h) and maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete. Findings: Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0·16-2·4 mg group n=12; 4·5 mg group n=11) or placebo (n=24), in combination with semaglutide 2·4 mg, of whom 95 were exposed to treatment (one patient in 0·60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40·6 years (SD 9·2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0·16-4·5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC0-168 h ranged from 926 nmol × h/L to 24 271 nmol × h/L, and Cmax ranged from 6·14 nmol/L to 170 nmol/L with cagrilintide 0·16-4·5 mg. AUC0-168 h ranged from 12 757 nmol × h/L to 15 305 nmol × h/L, and Cmax ranged from 96·4 nmol/L to 120 nmol/L with semaglutide 2·4 mg. Cagrilintide 0·16-4·5 mg had a half-life of 159-195 h, with a median tmax of 24-72 h. Semaglutide 2·4 mg had a half-life of 145-165 h, with a median tmax of 12-24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1·2 and 2·4 mg than with placebo (15·7% [SE 1·6] for cagrilintide 1·2 mg and 17·1% [1·5] for cagrilintide 2·4 mg vs 9·8% [1·2] for pooled placebo cohorts 1-5; estimated treatment difference of -6·0% [95% CI -9·9 to -2·0] for cagrilintide 1·2 mg and -7·4% [-11·2 to -3·5] for cagrilintide 2·4 mg vs pooled placebo), and with cagrilintide 4·5 mg than with matched placebo (15·4% [1·3] vs 8·0% [2·2]; estimated treatment difference -7·4% [-12·8 to -2·1]), all in combination with semaglutide 2·4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups. Interpretation: Concomitant treatment with cagrilintide and semaglutide 2·4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination. Funding: Novo Nordisk A/S.
Article
Background This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. Methods This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m² and glycated haemoglobin 7–10% (53–86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. Findings From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was −9·6% (SE 0·4) with semaglutide 2·4 mg vs −3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was −6·2 percentage points (95% CI −7·3 to −5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. Interpretation In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. Funding Novo Nordisk.
Article
Background Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. Methods In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. Results The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). Conclusions In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).
Article
Background Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known. Methods We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. Results In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed. Conclusions This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.)